This application addresses Challenge Area (06): Enabling Technologies and Specific Challenge Topic 06- HL-102, which is to develop high affinity/high specificity targeted molecular probes for molecular imaging of cardiovascular and pulmonary disease targets. We will use antibody probes to better define the pathogenesis of hypertriglyceridemia. Hypertriglyceridemia is caused by inherited defects in lipoprotein lipase (LPL), but the etiology of most cases of hypertriglyceridemia remains mysterious. Fortunately, recent discoveries on the mechanism by which LPL enters capillaries may uncloak the mystery. By applying new discoveries in lipolysis and molecular imaging, we will better define the underpinnings of hypertriglyceridemia. Reduced lipolysis by LPL underlies many cases of hypertriglyceridemia, but the explanation for the defective lipolysis is mysterious. This mystery is compounded when one considers the fact that many patients with hypertriglyceridemia have normal levels of LPL both in tissues and in the "postheparin" plasma. Arguably, the mechanisms for hypertriglyceridemia constitute the most perplexing riddle in lipoprotein metabolism. We have fresh insights into this problem. We identified an endothelial cell protein, GPIHBP1, which binds LPL and serves as a "platform" for the lipolysis in capillaries. Also, we found that GPIHBP1 serves as the "LPL transporter." GPIHBP1 transports LPL from the basolateral to the apical (luminal) surface of endothelial cells, where it hydro-lyzes lipoprotein triglycerides. We hypothesize that many cases of hypertriglyceridemia are due to defective GPIHBP1-mediated transport of LPL into capillaries. Drs. Stephen Young, Loren Fong, and colleagues have developed monoclonal and polyclonal antibodies against GPIHBP1 and LPL, as well as new gene-targeted models for assessing GPIHBP1 and LPL function. Meanwhile, Drs. Anna Wu and Tove Olafsen are pioneers in immunodiagnostics and molecular imaging. Together, we have already taken the first step and performed positron-based molecular imaging studies with an 124I-labeled monoclonal antibody against GPIHBP1. Over the next two years, we will develop molecular imaging approaches to measure the intracapillary levels of both GPIHBP1 and LPL. This topic can only be approached with molecular imaging techniques. Our imaging studies will begin with mouse models, but we will simultaneously prepare the reagents required for molecular analysis of lipolysis in humans. We expect that our efforts will clarify the mechanisms of hypertriglyceridemia and establish molecular imaging as a critical tool in understanding hypertriglyceridemia. H PUBLIC HEALTH RELEVANCE: Defective lipolysis can lead to atherosclerosis as well as life-threatening episodes of atherosclerosis. Genetic studies have shown that accelerated rates of lipolysis lead to lower plasma lipid levels and a reduced prevalence of coronary disease. Molecular imaging to define intracapillary levels of GPIHBP1 and LPL will lead to a vastly improved understanding of the molecular underpinnings of hypertriglyceridemia.